The present invention relates to the use of diazepinoindoles for the treatment of chronic obstructive pulmonary disease (hereinafter COPD).
COPD is a chronic, slowly progressive disorder characterized by airflow obstruction (associated with airways inflammation and an important neutrophil content). Most of the lung function impairment is fixed (although some reversibility can be produced by bronchodilator therapy). This disease will be referred to as COPD, although a number of clinical terms have been used in the past, either alone or in combination. These terms include emphysema, chronic bronchitis, chronic airflow limitation, chronic airways obstruction, non-reversible obstructive airways disease, chronic obstructive airways disease and chronic obstructive lung disease.
The clinical presentation of COPD can vary in severity from simple chronic bronchitis without disability to the severely disabled state with chronic respiratory failure. The major clinical features of patients suffering from COPD are chronic bronchitis and/or emphysema (associated with airways inflammation and/or an important neutrophil content).
Although the known prevalence of COPD is not complete, it can be ascertained that COPD is the fourth leading cause of death in developed countries, especially in the USA. Also, the problem of COPD is expected to grow, both in the developed western countries and in other countries in the coming years. A 3-fold increase is predicted to occur in the next ten years in the East Asia countries, as a large proportion of the male population is smoking.
Thus, there is a need for an efficient treatment of COPD.
In the past years, second-generation selective phosphodiesterase 4 inhibitors (PDE4 inhibitors) have been proposed as a potentially efficient treatment in COPD. See inter alia Doherty, Current Opinion in Chemical Biology 1999, 3:466-473; Mohammed et al, Anti-inflammatory and Immunomodulatory Investigational Drugs 1999 1(1):21-28; Schmidt et al., Clinical and Experimental Allergy, 29, supplement 2, 99-109.
Cilomilast (Ariflo(copyright)), an orally active PDE4 inhibitor, has been proposed as a treatment for COPD. See inter alia: Nieman et al, Am J Respir Crit Care Med 1998, 157:A413; Underwood et al, Eur Respir J 1998, 12:86s; Compton et al, Am J Respir Crit Care Med 1999, 159:A522. See also the oral presentations at the European Respiratory Society Meeting, Madrid, Oct. 12, 1999, by Compton, and at the 4th World Congress on Inflammation, Paris, Jun. 27-30, 1999, by Torphy and Underwood. This compound is currently in phase III clinical trials for COPD.
However, the use of cilomilast for treating COPD presents some drawbacks. It has been reported that when cilomilast is given at a single dose of 20 mg, relevant side effects such as nausea and vomiting occurred. See Murdoch et al, Am J Respir Crit Care Med 1998, 157:A409. Side effects appearing at such low dose will limit the application of cilomilast and will prevent daily single dosage forms, thus leading to patient discomfort.
The present invention proposes the use of a certain class of diazepinoindoles known as PDE4 inhibitors for the treatment of COPD. These compounds are devoid of adverse side effects, notably on the heart or digestive system (see Burnouf et al, Journal of medicinal chemistry (2000), 43:4850-4867), and are more efficient than cilomilast at lower doses.
The invention relates to the use of [1,4]diazepino[6,7,1-hi]indoles of formula (I) 
in which:
A is aryl or nitrogen-containing heteroaryl, each optionally being substituted with one to three groups chosen independently from halogen, lower alkyl, lower haloalkyl, lower alkoxy, cycloalkyloxy, amino and lower alkylcarbonyl-amino or alkyloxycarbonylamino;
B is a hydroxyl or amino radical, itself optionally substituted,
or a pharmaceutically acceptable salt thereof,
for the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease or COPD.
The invention also provides a method for the treatment of COPD comprising administering to a human in need thereof an effective amount of a diazepinoindole of formula I.
These compounds, their use as PDE4 inhibitors and their preparation processes are disclosed in WO 97/36905, the content of which is incorporated herein by reference. These diazepinoindoles will be used in the invention as the active ingredient.